title: Prediction and assessment of splicing alterations: implications for clinical testing.
abstract: Sequence variants that may result in splicing alterations are a particular class of inherited variants for which consequences can be more readily assessed, using a combination of bioinformatic prediction methods and in vitro assays. There is also a general agreement that a variant would invariably be considered pathogenic on the basis of convincing evidence that it results in transcript(s) carrying a premature stop codon or an in-frame deletion disrupting known functional domain(s). This commentary discusses current practices used to assess the clinical significance of this class of variants, provides suggestions to improve assessment, and highlights the issues involved in routine assessment of potential splicing aberrations. We conclude that classification of sequence variants that may alter splicing is greatly enhanced by supporting in vitro analysis. Additional studies that assess large numbers of variants for induction of splicing aberrations and exon skipping are needed to define the contribution of splicing/exon skipping to cancer and disease. These studies will also provide the impetus for development of algorithms that better predict splicing patterns. To facilitate variant classification and development of more specific bioinformatic tools, we call for the deposition of all laboratory data from splicing analyses into national and international databases.
authors.affiliation: Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia. Amanda.Spurdle@qimr.edu.au
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Olga M
authors.initials: OM
authors.lastname: Sinilnikova
mesh_terms: D000465:Algorithms; D017398:Alternative Splicing; D018389:Codon, Nonsense; D019295:Computational Biology / Q000379:methods*; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation; D006801:Humans; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense